JP2011251959A - Ambroxol-containing preparation particle - Google Patents
Ambroxol-containing preparation particle Download PDFInfo
- Publication number
- JP2011251959A JP2011251959A JP2011100277A JP2011100277A JP2011251959A JP 2011251959 A JP2011251959 A JP 2011251959A JP 2011100277 A JP2011100277 A JP 2011100277A JP 2011100277 A JP2011100277 A JP 2011100277A JP 2011251959 A JP2011251959 A JP 2011251959A
- Authority
- JP
- Japan
- Prior art keywords
- preparation
- ambroxol
- particles
- film layer
- coating
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000002245 particle Substances 0.000 title claims abstract description 142
- 238000002360 preparation method Methods 0.000 title claims abstract description 95
- 229960005174 ambroxol Drugs 0.000 title claims abstract description 29
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 title claims abstract description 28
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 19
- 238000009826 distribution Methods 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 239000000843 powder Substances 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 25
- 239000000454 talc Substances 0.000 claims description 25
- 229910052623 talc Inorganic materials 0.000 claims description 25
- 238000009472 formulation Methods 0.000 claims description 24
- 239000001856 Ethyl cellulose Substances 0.000 claims description 14
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 14
- 229920001249 ethyl cellulose Polymers 0.000 claims description 14
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 14
- 229920002678 cellulose Polymers 0.000 claims description 10
- 239000001913 cellulose Substances 0.000 claims description 10
- 239000007771 core particle Substances 0.000 claims description 10
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims description 8
- 235000012239 silicon dioxide Nutrition 0.000 claims description 8
- -1 aminoalkyl methacrylate Chemical compound 0.000 claims description 5
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 4
- 235000009508 confectionery Nutrition 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 2
- 238000010828 elution Methods 0.000 abstract description 24
- 239000003405 delayed action preparation Substances 0.000 abstract description 18
- 239000007888 film coating Substances 0.000 abstract description 13
- 238000009501 film coating Methods 0.000 abstract description 13
- 239000002775 capsule Substances 0.000 abstract description 5
- 239000008187 granular material Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 230000007721 medicinal effect Effects 0.000 abstract description 3
- 108010010803 Gelatin Proteins 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 238000000748 compression moulding Methods 0.000 abstract 1
- 239000002270 dispersing agent Substances 0.000 abstract 1
- 229920000159 gelatin Polymers 0.000 abstract 1
- 239000008273 gelatin Substances 0.000 abstract 1
- 235000019322 gelatine Nutrition 0.000 abstract 1
- 235000011852 gelatine desserts Nutrition 0.000 abstract 1
- 239000007902 hard capsule Substances 0.000 abstract 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 abstract 1
- 239000010408 film Substances 0.000 description 89
- 239000010410 layer Substances 0.000 description 61
- 239000011248 coating agent Substances 0.000 description 55
- 238000000576 coating method Methods 0.000 description 55
- 239000000243 solution Substances 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 30
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 30
- 239000008213 purified water Substances 0.000 description 24
- 238000013268 sustained release Methods 0.000 description 20
- 239000012730 sustained-release form Substances 0.000 description 20
- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 description 19
- 229960000985 ambroxol hydrochloride Drugs 0.000 description 19
- 229940079593 drug Drugs 0.000 description 19
- 239000003814 drug Substances 0.000 description 19
- 230000001681 protective effect Effects 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 238000004090 dissolution Methods 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 11
- 239000010419 fine particle Substances 0.000 description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 8
- 238000005507 spraying Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 230000003111 delayed effect Effects 0.000 description 6
- 238000005469 granulation Methods 0.000 description 6
- 230000003179 granulation Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000007903 gelatin capsule Substances 0.000 description 5
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 4
- 229910052782 aluminium Inorganic materials 0.000 description 4
- 239000011247 coating layer Substances 0.000 description 4
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 4
- 238000011049 filling Methods 0.000 description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 4
- 229960003943 hypromellose Drugs 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 3
- 238000007922 dissolution test Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 239000000654 additive Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 238000003889 chemical engineering Methods 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 208000014085 Chronic respiratory disease Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 238000012812 general test Methods 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 238000010030 laminating Methods 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 229920003176 water-insoluble polymer Polymers 0.000 description 1
Images
Abstract
Description
本発明は、有効成分としてアンブロキソール又はその塩を含有する製剤粒子に関し、該製剤粒子に非水溶性基剤をベースとしたフィルムコーティングを施した場合に、アンブロキソールの溶出が遅延し、溶出の制御が可能な徐放性製剤の提供を可能とする製剤粒子の組成、該製剤粒子の製造方法及びフィルムコーティングを施した該製剤粒子に関する。 The present invention relates to a preparation particle containing ambroxol or a salt thereof as an active ingredient, and when the preparation particle is subjected to a film coating based on a water-insoluble base, elution of ambroxol is delayed, The present invention relates to a composition of a preparation particle capable of providing a sustained-release preparation capable of controlling dissolution, a method for producing the preparation particle, and the preparation particle subjected to film coating.
気道潤滑去痰剤であるアンブロキソール又はその塩（例えば、アンブロキソール塩酸塩）は去痰に効果があり、急性気管支炎、気管支喘息、慢性気管支炎、かぜや呼吸疾患等の治療において汎用されている。慢性呼吸疾患患者の喀痰症状には日内変動があることが知られており、喀痰症状が出やすい早朝の時間帯に気道を痰の滑りやすい状態にするため、夕方服用し、早朝に効果が発現する徐放性製剤が用いられている（非特許文献１参照）。 Ambroxol or its salt (eg, ambroxol hydrochloride), an airway lubrication expectorant, is effective in expectoration and is widely used in the treatment of acute bronchitis, bronchial asthma, chronic bronchitis, colds, respiratory diseases, etc. Yes. It is known that there are diurnal fluctuations in epilepsy symptoms in patients with chronic respiratory disease, and it is taken in the evening to make the airway slippery in the early morning hours when epilepsy symptoms tend to occur. Sustained-release preparations are used (see Non-Patent Document 1).
アンブロキソール塩酸塩の場合、日本薬局方一般試験法溶出試験法第２法（パドル法）によって、試験液水、パドル回転数５０rpmの条件下に評価した場合、９０分後の薬物溶出率が２０〜５０％、１２０分後の薬物溶出率が３０〜６０％、及び３００分後の薬物溶出率が８０％以上であることが好ましいとされている（非特許文献２参照）。
In the case of ambroxol hydrochloride, when the drug dissolution rate after 90 minutes is evaluated by the Japanese Pharmacopoeia General Test Method Dissolution Test Method 2 (Paddle Method) under the conditions of test solution water and
ここで、徐放性製剤とは、製剤の投与後長時間に亘って薬物の有効血中濃度を維持できるように薬物の溶出が制御されている製剤である。 Here, the sustained-release preparation is a preparation in which elution of the drug is controlled so that the effective blood concentration of the drug can be maintained for a long time after administration of the preparation.
一般的な徐放性製剤としては、コーティング製剤が挙げられるが（非特許文献３参照）、コーティング製剤では、結晶セルロースシード等のコーティング用の核粒子が必要となる。核粒子上に薬物を積層造粒させて薬物含有粒子を製し、本粒子にフィルムコーティングして徐放化粒子を製するが、核粒子上に薬物を積層造粒させるために製剤が大型化することに加えて工程に非常に多くの時間を有するといった課題があった。 A general sustained-release preparation includes a coating preparation (see Non-Patent Document 3), but the coating preparation requires core particles for coating such as crystalline cellulose seed. A drug-containing particle is produced by laminating and granulating a drug on the core particle, and a sustained-release particle is produced by film-coating the main particle, but the preparation is enlarged because the drug is laminated and granulated on the core particle In addition to this, there is a problem that the process has a very long time.
本発明は、そのまま顆粒剤や散剤として服用したり、ゼラチン硬カプセルに封入してカプセル剤としたり、他の賦形剤と混合し圧縮成形して錠剤とする場合に、それらの製剤が大型化しない適度なサイズを有し、その製造にも多大の時間を要せず、フィルムコーティングを施した場合には、アンブロキソール又はその塩の溶出を遅延させ、アンブロキソールの薬効が投与直後から長時間に亘って持続する、アンブロキソール配合徐放性製剤を構成する製剤粒子を提供することを課題とする。 The present invention can be used as granules or powders as it is, encapsulated in hard gelatin capsules to form capsules, mixed with other excipients and compressed into tablets to increase the size of these preparations When the film coating is applied, the elution of ambroxol or a salt thereof is delayed, and the medicinal effect of ambroxol is immediately after administration. It is an object of the present invention to provide a preparation particle that constitutes an ambroxol-containing sustained-release preparation that lasts for a long time.
本発明者は、１日当たりの配合量が多く、徐放化に適する薬物としてアンブロキソール塩酸塩を採択し、このアンブロキソール塩酸塩を含有する核粒子を製してコーティングを施し、溶出特性について鋭意検討を行った。その結果、アンブロキソール塩酸塩を含有する核粒子の調製方法として、ショ糖シードなど賦形剤核を使わずに、アンブロキソール塩酸塩と賦形剤とからなる核粒子に該当する製剤を調製し、この製剤にヒドロキシプロピルメチルセルロースを含有する保護膜をコーティングした後、エチルセルロース等の水不溶性高分子を基剤とするフィルムコーティングを施すことにより、アンブロキソールの溶出が遅延し、徐放化しうることを見出した。 The present inventor adopted ambroxol hydrochloride as a drug that has a large amount per day and is suitable for sustained release, produced core particles containing this ambroxol hydrochloride, applied the coating, and elution characteristics We conducted an intensive study. As a result, as a method for preparing the core particle containing ambroxol hydrochloride, a preparation corresponding to the core particle composed of ambroxol hydrochloride and excipient is used without using an excipient nucleus such as sucrose seed. After preparing and coating this preparation with a protective film containing hydroxypropylmethylcellulose, by applying a film coating based on a water-insoluble polymer such as ethylcellulose, the elution of ambroxol is delayed and sustained release I found out.
かかる知見に基づき完成した本発明の態様は、賦形剤のみからなる核粒子がなく、アンブロキソール又はその塩と賦形剤とからなり、平均粒子径が４００〜１０００μｍで、粒度分布の幾何標準偏差が１．５以下であることを特徴とする製剤粒子である。 The embodiment of the present invention completed on the basis of such findings has no core particles consisting only of excipients, is composed of ambroxol or a salt thereof and excipients, has an average particle size of 400 to 1000 μm, and has a geometry of particle size distribution. A preparation particle having a standard deviation of 1.5 or less.
本発明の他の態様は、賦形剤として、アメ粉、マルトース、タルク、結晶セルロース及びケイ酸の少なくとも１種を含有する前記製剤粒子である。 The other aspect of this invention is the said formulation particle | grains containing at least 1 sort (s) of a candy powder, maltose, a talc, a crystalline cellulose, and a silicic acid as an excipient | filler.
本発明の他の態様は、エチルセルロース又はアミノアルキルメタアクリレートを含有するフィルム層で被覆されていることを特徴とする前記製剤粒子である。 Another aspect of the present invention is the above-mentioned preparation particle, which is coated with a film layer containing ethyl cellulose or aminoalkyl methacrylate.
本発明により、賦形剤のみからなる核粒子がなく、アンブロキソール又はその塩を含有し、エチルセルロース又はアミノアルキルメタアクリレートを含有するフィルム層で被覆したときに、アンブロキソールの溶出が遅延する製剤粒子を提供することが可能となった。 According to the present invention, the dissolution of ambroxol is delayed when there is no core particle consisting only of excipients, and it is coated with a film layer containing ambroxol or a salt thereof and containing ethylcellulose or aminoalkyl methacrylate. It became possible to provide formulation particles.
本発明における「製剤粒子」は、アンブロキソール又はその塩と賦形剤を含有し、平均粒子径が４００〜１０００μｍで、粒度分布の幾何標準偏差が１．５以下の粒子である。該粒子はエチルセルロースやアミノアルキルメタアクリレートといった水不溶性のコーティング基剤を配合したフィルムコーティング液でコーティングし、フィルム層で被覆した場合に、有効成分であるアンブロキソールの溶出が遅延し、徐放性製剤を提供する際の徐放化粒子として好適である。該製剤粒子の具体的な物性は次のとおりである。 The “formulation particles” in the present invention are particles containing ambroxol or a salt thereof and an excipient, having an average particle size of 400 to 1000 μm and a geometric standard deviation of particle size distribution of 1.5 or less. When the particles are coated with a film coating solution containing a water-insoluble coating base such as ethyl cellulose or aminoalkyl methacrylate, and coated with a film layer, the elution of the active ingredient ambroxol is delayed and sustained release Suitable as sustained release particles when providing a formulation. Specific physical properties of the preparation particles are as follows.
製剤粒子の平均粒子径は４００μｍ以上１０００μｍ以下、粒度分布の幾何標準偏差は１．５以下である。 The average particle size of the preparation particles is 400 μm or more and 1000 μm or less, and the geometric standard deviation of the particle size distribution is 1.5 or less.
「平均粒子径（mean particle diameter）」とは、質量平均径である。具体的には、サンプリングした粒子（例えば５ｇ）を、１０Ｍ（１７００μｍ）、１２Ｍ（１４００μｍ）、１６Ｍ（１０００μｍ）、２０Ｍ（８５０μｍ）、２４Ｍ（７１０μｍ）、２８Ｍ（６００μｍ）、３２Ｍ（５００μｍ）及び３５Ｍ（４２５μｍ）の順に積み重ねた篩上に置き、一定時間（例えば、３分間）振動を与えて分級し、１０Ｍ篩残、１２Ｍ篩残、１６Ｍ篩残、２０Ｍ篩残、２４Ｍ篩残、２８Ｍ篩残、３２Ｍ篩残、３５Ｍ篩残及び３５Ｍ通過分の各質量を測定する。各質量に、予め算出しておいた各篩間の粒径区分の中央値を乗じ、その総和を全質量（５ｇ）で除した値が求める質量平均径、すなわち、本発明における平均粒子径である。例えば、ロッボットシフター（株式会社セイシン企業）などを用いれば自動的に測定できる。なお、Ｍはメッシュを表す。 The “mean particle diameter” is the mass average diameter. Specifically, the sampled particles (for example, 5 g) are 10M (1700 μm), 12M (1400 μm), 16M (1000 μm), 20M (850 μm), 24M (710 μm), 28M (600 μm), 32M (500 μm) and 35M. Place on a sieve stacked in the order of (425 μm), apply vibration for a certain time (for example, 3 minutes), classify, 10M sieve residue, 12M sieve residue, 16M sieve residue, 20M sieve residue, 24M sieve residue, 28M sieve residue , 32M sieve residue, 35M sieve residue and 35M passing mass are measured. Multiply each mass by the median value of the particle size classification between each sieve that has been calculated in advance, and obtain the mass average diameter obtained by dividing the sum by the total mass (5 g), that is, the average particle size in the present invention. is there. For example, it can be automatically measured by using a robot shifter (seishin corporation). M represents a mesh.
「粒度分布（粒径分布）」とは、ある粒径範囲に属する粒子の粉体全量に対する割合をいう。具体的には、前記と同様にサンプリングした粒子（例えば５ｇ）を、１０Ｍ（１７００μｍ）、１２Ｍ（１４００μｍ）、１６Ｍ（１０００μｍ）、２０Ｍ（８５０μｍ）、２４Ｍ（７１０μｍ）、２８Ｍ（６００μｍ）、３２Ｍ（５００μｍ）及び３５Ｍ（４２５μｍ）の順に積み重ねた篩上に置き、一定時間（例えば、３分間）振動を与えて分級し、１０Ｍ篩残、１２Ｍ篩残、１６Ｍ篩残、２０Ｍ篩残、２４Ｍ篩残、２８Ｍ篩残、３２Ｍ篩残、３５Ｍ篩残及び３５Ｍ通過分の各質量を測定する。各質量を全質量（５ｇ）で除し、１００を乗じて質量％で表される。コーティング用核粒子としての用途を斟酌すると、その「幾何標準偏差（geometric standard deviation）」は、１．５以下が好ましい。ここに、幾何標準偏差は、対数正規分布により求められる積算通過分率８４．１３％のときの粒径を積算通過分率５０％のときの粒径（中位径または幾何平均径）で除したときの値である。 “Particle size distribution (particle size distribution)” refers to the ratio of particles belonging to a certain particle size range to the total amount of powder. Specifically, the particles (for example, 5 g) sampled in the same manner as described above are 10M (1700 μm), 12M (1400 μm), 16M (1000 μm), 20M (850 μm), 24M (710 μm), 28M (600 μm), 32M ( 500 μm) and 35 M (425 μm) in order, placed on a sieve stacked in order, given vibration for a certain time (for example, 3 minutes), classified, 10M sieve residue, 12M sieve residue, 16M sieve residue, 20M sieve residue, 24M sieve residue , 28M sieve residue, 32M sieve residue, 35M sieve residue and 35M passing mass are measured. Each mass is divided by the total mass (5 g) and multiplied by 100 and expressed in mass%. Considering the use as a core particle for coating, the “geometric standard deviation” is preferably 1.5 or less. Here, the geometric standard deviation is obtained by dividing the particle diameter when the cumulative passage fraction is 84.13% obtained by the logarithmic normal distribution by the particle diameter (median diameter or geometric mean diameter) when the cumulative passage fraction is 50%. This is the value when
「平衡相対湿度（ＥＲＨ）」とは、本発明の固形製剤約０．１ｇを２５℃の密閉容器内に置いた場合の、その密閉容器内空間が示す平衡相対湿度（ＥＲＨ）を意味し、
式：平衡相対湿度（ＥＲＨ）＝（Ｐ／ＰＳ）×１００［式中、Ｐは物質の表面上の水蒸気圧を示し、ＰＳは物質と同じ温度における純水上の水蒸気圧を示す。］
で求めることができる。例えば、水分活性測定用装置ＴＨ−５００（DKSHジャパン株式会社）などを用いれば自動的に測定できる。
“Equilibrium relative humidity (ERH)” means the equilibrium relative humidity (ERH) indicated by the space in the sealed container when about 0.1 g of the solid preparation of the present invention is placed in a sealed container at 25 ° C.
Formula: Equilibrium relative humidity (ERH) = (P / PS) × 100 [where P represents the water vapor pressure on the surface of the substance, and PS represents the water vapor pressure on pure water at the same temperature as the substance. ]
Can be obtained. For example, it can be automatically measured using a water activity measuring device TH-500 (DKSH Japan Co., Ltd.).
なお、平均粒子径、粒度分布、幾何学標準偏差については、社団法人化学工学会編「現代の化学工学Ｉ」（１９８８年、朝倉書店、ｐ．２３９〜ｐ．２４５）に依った。 The average particle size, particle size distribution, and geometric standard deviation depended on “Modern Chemical Engineering I” (1988, Asakura Shoten, p. 239 to p. 245) edited by the Japan Society for Chemical Engineering.
「アンブロキソール又はその塩」の含有（配合）量は製剤粒子全体の５．０〜９０質量％である。５．０質量％未満では製剤中のアンブロキソールの配合量が少なすぎて、アンブロキソール高含有製剤を目的とする本発明を用いる意義に乏しく、９０質量％を超えると賦形剤の配合量が少なすぎて、所望の大きさ、平均粒子径、粒子強度等を有し、フィルムコーティングに適する製剤粒子を得ることが極めて難しいからである。 The content (formulation) of “ambroxol or a salt thereof” is 5.0 to 90% by mass of the entire preparation particle. If it is less than 5.0% by mass, the amount of ambroxol in the preparation is too small, and it is not meaningful to use the present invention for the preparation containing a high amount of ambroxol. This is because the amount is too small, and it is extremely difficult to obtain preparation particles having a desired size, average particle diameter, particle strength and the like and suitable for film coating.
本発明においてアンブロキソール又はその塩とともに配合される「賦形剤」としては、アメ粉、マルトース、タルク、結晶セルロース、ケイ酸、酸化チタン、ヒドロキシプロピルメチルセルロース（ヒプロメロースともいう）、ヒドロキシプロピルセルロースが挙げられる。このうち、アメ粉、マルトース、タルク、結晶セルロース及びケイ酸の少なくとも１種は粒子の形成及びその球形化のために配合することが好ましく、その製剤粒子中の含有（配合）量は１０〜９５質量％である。１０質量未満であると、所望の大きさ、平均粒子径、粒子強度等を有し、フィルムコーティングに適する製剤粒子を得ることが難しく、９５質量％を超えると、アンブロキソールの配合量が少なくなり、アンブロキソール高含有製剤を目的とする本発明を用いる意義に乏しいからである。 Examples of the “excipient” blended with ambroxol or a salt thereof in the present invention include candy powder, maltose, talc, crystalline cellulose, silicic acid, titanium oxide, hydroxypropylmethylcellulose (also referred to as hypromellose), and hydroxypropylcellulose. Can be mentioned. Among these, at least one of candy powder, maltose, talc, crystalline cellulose, and silicic acid is preferably blended for the formation of particles and spheroidization thereof, and the content (blending) amount in the formulation particles is 10 to 95. % By mass. If it is less than 10 mass, it is difficult to obtain pharmaceutical particles having a desired size, average particle diameter, particle strength, etc. and suitable for film coating. If it exceeds 95 mass%, the amount of ambroxol is small. This is because the significance of using the present invention aimed at a high-ambroxol-containing preparation is poor.
本発明の製剤粒子はそのままではアンブロキソールの溶出遅延を生じない。徐放化粒子として提供するためには、フィルムコーティングを施す必要がある。一般的に顆粒や錠剤にフィルムコーティングを施して薬物の溶出を遅延させる作用を有する基剤であれば、どのような基剤であっても構わないが、エチルセルロースやアミノアルキルメタアクリレートのような水不溶性のコーティング基剤が好ましい。そして、被覆量が多くなり、フィルム層が厚くなれば、アンブロキソールの溶出は遅延するので、フィルムコーティングしていない製剤粒子とフィルム層で被覆された１種又は２種以上の製剤粒子を適宜に組み合わせることにより、溶出パターンの異なる、アンブロキソールの薬効が持続する徐放性製剤を提供することができる。 The formulation particles of the present invention as they are do not cause a delay in the dissolution of ambroxol. In order to provide as sustained release particles, a film coating must be applied. In general, any base may be used as long as it has a function of delaying the dissolution of a drug by film coating on granules or tablets, but water such as ethyl cellulose or aminoalkyl methacrylate may be used. Insoluble coating bases are preferred. When the coating amount increases and the film layer becomes thicker, the elution of ambroxol is delayed. Therefore, the formulation particles not coated with the film and one or more formulation particles coated with the film layer are appropriately selected. In combination, it is possible to provide a sustained-release preparation having a different dissolution pattern and maintaining the efficacy of ambroxol.
製剤粒子の製造方法としては、例えば、アンブロキソール塩酸塩、タルク、軽質無水ケイ酸、結晶セルロース、糖類系賦形剤を混合、粉砕して造粒用粉末を調製する。該造粒用粉末を転動（撹拌）流動層造粒機中に転動（撹拌）流動させ、該造粒用粉末に水に結合剤を溶解させた結合液を噴霧し、乾燥、分級して目的とする製剤粒子を調製するという方法が挙げられる。また、本発明の効果を損なわない範囲で、該製剤粒子に他の有効成分及び公知の添加剤を配合することができる。公知の添加剤としては、日本医薬品添加剤協会編「医薬品添加物事典２００７」（２００７年、薬事日報社）に収載されている添加剤等が挙げられる。 As a method for producing the preparation particles, for example, ambroxol hydrochloride, talc, light silicic anhydride, crystalline cellulose, and saccharide excipient are mixed and pulverized to prepare a granulating powder. The granulating powder is tumbled (stirred) and fluidized in a rolling (stirring) fluidized bed granulator, and the granulated powder is sprayed with a binding solution in which a binder is dissolved in water, dried and classified. And preparing the desired preparation particles. In addition, other active ingredients and known additives can be blended with the preparation particles as long as the effects of the present invention are not impaired. Known additives include those listed in “Pharmaceutical Additives Encyclopedia 2007” edited by Japan Pharmaceutical Additives Association (2007, Yakuji Nippo).
また、フィルム層で被覆された製剤粒子とフィルム層で被覆されていない製剤粒子を混合して、散剤又は顆粒剤として徐放性製剤を提供できる他、これをゼラチンや高分子のハードカプセルに充填し、徐放性のカプセル剤として提供したり、フィルム層で被覆された製剤粒子を他の賦形剤等と混合し、これを圧縮成形（打錠）することによって、徐放性の錠剤として提供することも可能である。 In addition, preparation particles coated with a film layer and preparation particles not coated with a film layer can be mixed to provide a sustained-release preparation as a powder or granule. Provided as sustained-release capsules, or as a sustained-release tablet by mixing formulation particles coated with film layers with other excipients and compressing them (tablet) It is also possible to do.
以下に、実施例、比較例及び試験例を挙げ、本発明を更に詳細に説明する。 Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples.
実施例１
（１）造粒用粉末の調製
アンブロキソール塩酸塩 ４９５．０ｇ
タルク ９９．０ｇ
軽質無水ケイ酸 １０．０ｇ
結晶セルロース １９８．０ｇ
アメ粉 １９８．０ｇ
上記成分を秤量後、混合・粉砕し、均一な造粒用粉末を得た。
（２）結合液の調製
ヒドロキシプロピルメチルセルロース（ヒプロメロース） ８４．０ｇ
精製水 １０３６．０ｇ
精製水にヒドロキシプロピルメチルセルロース（ヒプロメロース；以下、「ＨＰＭＣ」と略記する。）を溶解させ、結合液を得た。
（３）製剤粒子の調製
造粒用粉末を転動流動コーティング装置（商品名：マルチプレックス；パウレック社製）に１６７ｇ充填し、前記結合液と造粒用粉末３３３ｇを噴霧しながら造粒し、乾燥後１７００μｍの篩で分級して、製剤粒子を得た。
得られた製剤粒子は、平均粒子径４３２μｍ、粒度分布の幾何標準偏差は１．３４８であった。
（４）１次コーティング液の調製
ＨＰＭＣ ２０．０ｇ
タルク ５．０ｇ
精製水 ２８７．５ｇ
精製水にＨＰＭＣを溶解させ、タルクを分散させて１次コーティング液を調製した。
（５）１次コーティング層（保護膜）の被覆
上記で得られた製剤粒子５００ｇを微粒子コーティング装置（商品名：ＧＰＣＧ；パウレック社製）に充填し、前記１次コーティング液を３１３ｇスプレー噴霧し、１次フィルム層（保護膜）を施した。
（６）２次コーティング液の調製
エチルセルロース ３６．７５ｇ
ＨＰＭＣ ５．２５ｇ
タルク １０．５０ｇ
エタノール ５２５．６０ｇ
精製水 １３１．４０ｇ
エタノールと精製水の混液にエチルセルロースとＨＰＭＣを溶解させ、タルクを分散させて２次コーティング液を調製した。
（７）フィルム層で被覆された製剤粒子の調製（２次フィルム層（徐放膜）の被覆）
１次フィルム層（保護膜）を施した製剤粒子５２５ｇを微粒子コーティング装置に充填し、前記２次コーティング液を７０９．５ｇスプレー噴霧し、２次フィルム層（徐放膜）を施して、フィルム層で被覆された製剤粒子を得た。
得られたフィルム層で被覆された製剤粒子は、平均粒子径４０４μｍ、粒度分布の幾何標準偏差は１．３６９であった。
なお、製剤粒子をゼラチンカプセルに封入し、４０℃７５％ＲＨ環境下にてアルミピロー包装して保存した場合における平衡相対湿度（ＥＲＨ）は、製造直後２７．７％、１カ月後２９．７％、３カ月後３１．７％、６カ月後３５．５％であった。
Example 1
(1) Preparation of granulating powder Ambroxol hydrochloride 495.0 g
Talc 99.0g
Light anhydrous silicic acid 10.0g
Crystalline cellulose 198.0g
American powder 198.0g
After weighing the above components, they were mixed and pulverized to obtain a uniform granulating powder.
(2) Preparation of binding solution 84.0 g of hydroxypropyl methylcellulose (hypromellose)
Purified water 1036.0g
Hydroxypropyl methylcellulose (hypromellose; hereinafter abbreviated as “HPMC”) was dissolved in purified water to obtain a binding solution.
(3) Preparation of formulation particles 167 g of the granulating powder is loaded into a tumbling fluidized coating apparatus (trade name: Multiplex; manufactured by POWREC), and granulated while spraying the binding solution and 333 g of the granulating powder. After drying, it was classified with a 1700 μm sieve to obtain preparation particles.
The obtained preparation particles had an average particle diameter of 432 μm and a geometric standard deviation of the particle size distribution of 1.348.
(4) Preparation of primary coating solution HPMC 20.0 g
Talc 5.0g
287.5g of purified water
HPMC was dissolved in purified water and talc was dispersed to prepare a primary coating solution.
(5) Coating of primary coating layer (protective film) 500 g of the preparation particles obtained above were filled in a fine particle coating apparatus (trade name: GPCG; manufactured by POWREC), and 313 g of the primary coating solution was sprayed. A primary film layer (protective film) was applied.
(6) Preparation of secondary coating solution 36.75 g of ethyl cellulose
HPMC 5.25g
Talc 10.50g
Ethanol 525.60g
Purified water 131.40g
Ethyl cellulose and HPMC were dissolved in a mixed solution of ethanol and purified water, and talc was dispersed to prepare a secondary coating solution.
(7) Preparation of formulation particles coated with film layer (coating of secondary film layer (sustained release film))
Filling the fine particle coating device with 525 g of the preparation particles with the primary film layer (protective film), spraying the above-mentioned secondary coating solution with 709.5 g, and applying the secondary film layer (sustained release film), the film layer Preparation particles coated with were obtained.
The preparation particles coated with the obtained film layer had an average particle size of 404 μm and a geometric standard deviation of the particle size distribution of 1.369.
The equilibrium relative humidity (ERH) when the preparation particles are enclosed in a gelatin capsule and stored in an aluminum pillow package at 40 ° C. and 75% RH is 27.7% immediately after production and 29.7 after one month. %, 31.7% after 3 months, and 35.5% after 6 months.
実施例２
（１）造粒用粉末の調製
アンブロキソール塩酸塩 ４９５．０ｇ
タルク ９９．０ｇ
軽質無水ケイ酸 １０．０ｇ
結晶セルロース １９８．０ｇ
アメ粉 １９８．０ｇ
上記成分を秤量後、混合・粉砕し、均一な造粒用粉末を得た。
（２）結合液の調製
ＨＰＭＣ ８４．０ｇ
精製水 １０３６．０ｇ
精製水にＨＰＭＣを溶解させ、結合液を得た。
（３）製剤粒子の調製
造粒用粉末を転動流動コーティング装置に１６７ｇ充填し、前記結合液と造粒用粉末３３３ｇを噴霧しながら造粒し、乾燥後１７００μｍの篩で分級して、製剤粒子を得た。
得られた製剤粒子は、平均粒子径６３１μｍ、粒度分布の幾何標準偏差は１．４９０であった。
（４）１次コーティング液の調製
ＨＰＭＣ ２０．０ｇ
タルク ５．０ｇ
精製水 ２８７．５ｇ
精製水にＨＰＭＣを溶解させ、タルクを分散させて１次コーティング液を調製した。
（５）１次コーティング層（保護膜）の被覆
上記で得られた製剤粒子５００ｇを微粒子コーティング装置に充填し、前記１次コーティング液を３１３ｇスプレー噴霧し、１次フィルム層（保護膜）を施した。
（６）２次コーティング液の調製
エチルセルロース １８．３７５ｇ
ＨＰＭＣ ２．６２５ｇ
タルク ５．２５０ｇ
エタノール ２６２．８０ｇ
精製水 ６５．７０ｇ
エタノールと精製水の混液にエチルセルロースとＨＰＭＣを溶解させ、タルクを分散させて２次コーティング液を調製した。
（７）フィルム層で被覆された製剤粒子の調製（２次フィルム層（徐放膜）の被覆）
１次フィルム層（保護膜）を施した製剤粒子５２５ｇを微粒子コーティング装置に充填し、前記２次コーティング液を３４４．７５ｇスプレー噴霧し、２次フィルム層（徐放膜）を施して、フィルム層で被覆された製剤粒子を得た。
得られたフィルム層で被覆された製剤粒子は、平均粒子径５４９μｍ、粒度分布の幾何標準偏差は１．４０１であった。
Example 2
(1) Preparation of granulating powder Ambroxol hydrochloride 495.0 g
Talc 99.0g
Light anhydrous silicic acid 10.0g
Crystalline cellulose 198.0g
American powder 198.0g
After weighing the above components, they were mixed and pulverized to obtain a uniform granulating powder.
(2) Preparation of binding solution 84.0 g HPMC
Purified water 1036.0g
HPMC was dissolved in purified water to obtain a binding solution.
(3) Preparation of formulation particles 167g of granulation powder is packed in a tumbling fluidized coating device, granulated while spraying the binding liquid and 333g of granulation powder, dried and classified with a 1700μm sieve, Particles were obtained.
The obtained preparation particles had an average particle diameter of 631 μm and a geometric standard deviation of the particle size distribution of 1.490.
(4) Preparation of primary coating solution HPMC 20.0 g
Talc 5.0g
287.5g of purified water
HPMC was dissolved in purified water and talc was dispersed to prepare a primary coating solution.
(5) Coating of primary coating layer (protective film) 500 g of the preparation particles obtained above are filled in a fine particle coating apparatus, and 313 g of the primary coating solution is sprayed to apply a primary film layer (protective film). did.
(6) Preparation of secondary coating solution 18.375 g of ethyl cellulose
HPMC 2.625g
Talc 5.250g
Ethanol 262.80 g
65.70 g of purified water
Ethyl cellulose and HPMC were dissolved in a mixed solution of ethanol and purified water, and talc was dispersed to prepare a secondary coating solution.
(7) Preparation of formulation particles coated with film layer (coating of secondary film layer (sustained release film))
Filling the fine particle coating device with 525 g of the preparation particles with the primary film layer (protective film), spraying 344.75 g of the secondary coating liquid, and applying the secondary film layer (sustained release film), the film layer Preparation particles coated with were obtained.
The obtained preparation particles coated with the film layer had an average particle size of 549 μm and a geometric standard deviation of the particle size distribution of 1.401.
比較例１
（１）造粒用粉末の調製
アンブロキソール塩酸塩 ４９５．０ｇ
タルク ９９．０ｇ
軽質無水ケイ酸 １０．０ｇ
結晶セルロース １９８．０ｇ
アメ粉 １９８．０ｇ
上記成分を秤量後、混合・粉砕し、均一な造粒用粉末を得た。
（２）結合液の調製
ＨＰＭＣ ８４．０ｇ
精製水 １０３６．０ｇ
精製水にＨＰＭＣを溶解させ、結合液を得た。
（３）製剤粒子の調製
造粒用粉末を転動流動コーティング装置に１６７ｇ充填し、前記結合液と造粒用粉末３３３ｇを噴霧しながら造粒し、乾燥後１７００μｍの篩で分級して、製剤粒子を得た。
得られた製剤粒子は、平均粒子径１６０μｍ、粒度分布の幾何標準偏差は１．５９１であった。
（４）１次コーティング液の調製
ＨＰＭＣ ２０．０ｇ
タルク ５．０ｇ
精製水 ２８７．５ｇ
精製水にＨＰＭＣを溶解させ、タルクを分散させて１次コーティング液を調製した。
（５）１次コーティング層（保護膜）の被覆
上記で得られた製剤粒子５００ｇを微粒子コーティング装置に充填し、前記１次コーティング液を３１３ｇスプレー噴霧し、１次フィルム層（保護膜）を施した。
（６）２次コーティング液の調製
エチルセルロース ５５．１２５ｇ
ＨＰＭＣ ７．８７５ｇ
タルク １５．７５０ｇ
エタノール ７８８．４０ｇ
精製水 １９７．１０ｇ
エタノールと精製水の混液にエチルセルロースとＨＰＭＣを溶解させ、タルクを分散させて２次コーティング液を調製した。
（７）フィルム層で被覆された製剤粒子の調製（２次フィルム層（徐放膜）の被覆）
１次フィルム層（保護膜）を施した製剤粒子５２５ｇを微粒子コーティング装置に充填し、前記２次コーティング液を１０６４．２５ｇスプレー噴霧し、２次フィルム層（徐放膜）を施して、フィルム層で被覆された製剤粒子を得た。
得られたフィルム層で被覆された製剤粒子は、平均粒子径１４４μｍ、粒度分布の幾何標準偏差は１．５２６であった。
なお、溶出特性を評価するために、１次フィルム層（保護膜）を施した製剤粒子に対して、２次フィルム層（徐放膜）を固形分として５質量％及び１０質量％施した時点でのフィルム層で被覆された製剤粒子をサンプリングした。
Comparative Example 1
(1) Preparation of granulating powder Ambroxol hydrochloride 495.0 g
Talc 99.0g
Light anhydrous silicic acid 10.0g
Crystalline cellulose 198.0g
American powder 198.0g
After weighing the above components, they were mixed and pulverized to obtain a uniform granulating powder.
(2) Preparation of binding solution 84.0 g HPMC
Purified water 1036.0g
HPMC was dissolved in purified water to obtain a binding solution.
(3) Preparation of formulation particles 167g of granulation powder is packed in a tumbling fluidized coating device, granulated while spraying the binding liquid and 333g of granulation powder, dried and classified with a 1700μm sieve, Particles were obtained.
The obtained preparation particles had an average particle size of 160 μm and a geometric standard deviation of the particle size distribution of 1.591.
(4) Preparation of primary coating solution HPMC 20.0 g
Talc 5.0g
287.5g of purified water
HPMC was dissolved in purified water and talc was dispersed to prepare a primary coating solution.
(5) Coating of primary coating layer (protective film) 500 g of the preparation particles obtained above are filled in a fine particle coating apparatus, and 313 g of the primary coating solution is sprayed to apply a primary film layer (protective film). did.
(6) Preparation of secondary coating solution 55.125 g of ethyl cellulose
HPMC 7.875g
Talc 15.750g
Ethanol 788.40g
197.10 g of purified water
Ethyl cellulose and HPMC were dissolved in a mixed solution of ethanol and purified water, and talc was dispersed to prepare a secondary coating solution.
(7) Preparation of formulation particles coated with film layer (coating of secondary film layer (sustained release film))
Filling the fine particle coating device with 525 g of the preparation particles with the primary film layer (protective film), spray spraying 1064.25 g of the secondary coating liquid, and applying the secondary film layer (sustained release film) to form the film layer Preparation particles coated with were obtained.
The preparation particles coated with the obtained film layer had an average particle size of 144 μm and a geometric standard deviation of the particle size distribution of 1.526.
In addition, in order to evaluate the elution characteristics, when the secondary film layer (sustained release film) was applied at 5% by mass and 10% by mass as the solid content to the preparation particles subjected to the primary film layer (protective film). The formulation particles coated with the film layer at were sampled.
比較例２
（１）造粒用粉末の調製
アンブロキソール塩酸塩 ４９５．０ｇ
タルク ９９．０ｇ
軽質無水ケイ酸 １０．０ｇ
結晶セルロース １９８．０ｇ
アメ粉 １９８．０ｇ
上記成分を秤量後、混合・粉砕し、均一な造粒用粉末を得た。
（２）結合液の調製
ＨＰＭＣ ８４．０ｇ
精製水 １０３６．０ｇ
精製水にＨＰＭＣを溶解させ、結合液を得た。
（３）製剤粒子の調製
造粒用粉末を転動流動コーティング装置に１６７ｇ充填し、前記結合液と造粒用粉末３３３ｇを噴霧しながら造粒し、乾燥後１７００μｍの篩で分級して、製剤粒子を得た。
得られた製剤粒子は、平均粒子径１０４１μｍ、粒度分布の幾何標準偏差は１．２４９であった。
（４）１次コーティング液の調製
ＨＰＭＣ ２０．０ｇ
タルク ５．０ｇ
精製水 ２８７．５ｇ
精製水にヒプロメロースを溶解させ、タルクを分散させて１次コーティング液を調製した。
（５）１次コーティング層（保護膜）の被覆
上記で得られた製剤粒子５００ｇを微粒子コーティング装置に充填し、前記１次コーティング液を３１３ｇスプレー噴霧し、１次フィルム層（保護膜）を施した。
（６）２次コーティング液の調製
エチルセルロース ５５．１２５ｇ
ＨＰＭＣ ７．８７５ｇ
タルク １５．７５０ｇ
エタノール ７８８．４０ｇ
精製水 １９７．１０ｇ
エタノールと精製水の混液にエチルセルロースとＨＰＭＣを溶解させ、タルクを分散させて２次コーティング液を調製した。
（７）フィルム層で被覆された製剤粒子の調製（２次フィルム層（徐放膜）の被覆）
１次フィルム層（保護膜）を施した製剤粒子５２５ｇを微粒子コーティング装置に充填し、前記２次コーティング液を１０６４．２５ｇスプレー噴霧し、２次フィルム層（徐放膜）を施して、フィルム層で被覆された製剤粒子を得た。
得られたフィルム層で被覆された製剤粒子は、平均粒子径１０６２μｍ、粒度分布の幾何標準偏差は１．２４２であった。
なお、溶出特性を評価するために、１次フィルム層（保護膜）を施した製剤粒子に対して、２次フィルム層（徐放膜）を固形分として５質量％及び１０質量％施した時点でのフィルム層で被覆された製剤粒子をサンプリングした。
Comparative Example 2
(1) Preparation of granulating powder Ambroxol hydrochloride 495.0 g
Talc 99.0g
Light anhydrous silicic acid 10.0g
Crystalline cellulose 198.0g
American powder 198.0g
After weighing the above components, they were mixed and pulverized to obtain a uniform granulating powder.
(2) Preparation of binding solution 84.0 g HPMC
Purified water 1036.0g
HPMC was dissolved in purified water to obtain a binding solution.
(3) Preparation of formulation particles 167g of granulation powder is packed in a tumbling fluidized coating device, granulated while spraying the binding liquid and 333g of granulation powder, dried and classified with a 1700μm sieve, Particles were obtained.
The resulting preparation particles had an average particle size of 1041 μm and a geometric standard deviation of the particle size distribution of 1.249.
(4) Preparation of primary coating solution HPMC 20.0 g
Talc 5.0g
287.5g of purified water
Hypromellose was dissolved in purified water and talc was dispersed to prepare a primary coating solution.
(5) Coating of primary coating layer (protective film) 500 g of the preparation particles obtained above are filled in a fine particle coating apparatus, and 313 g of the primary coating solution is sprayed to apply a primary film layer (protective film). did.
(6) Preparation of secondary coating solution 55.125 g of ethyl cellulose
HPMC 7.875g
Talc 15.750g
Ethanol 788.40g
197.10 g of purified water
Ethyl cellulose and HPMC were dissolved in a mixed solution of ethanol and purified water, and talc was dispersed to prepare a secondary coating solution.
(7) Preparation of formulation particles coated with film layer (coating of secondary film layer (sustained release film))
Filling the fine particle coating device with 525 g of the preparation particles with the primary film layer (protective film), spray spraying 1064.25 g of the secondary coating liquid, and applying the secondary film layer (sustained release film) to form the film layer Preparation particles coated with were obtained.
The preparation particles coated with the obtained film layer had an average particle size of 1062 μm and a geometric standard deviation of the particle size distribution of 1.242.
In addition, in order to evaluate the elution characteristics, when the secondary film layer (sustained release film) was applied at 5% by mass and 10% by mass as the solid content to the preparation particles subjected to the primary film layer (protective film). The formulation particles coated with the film layer at were sampled.
試験例１ 溶出試験
（１）方法
実施例１、実施例２、比較例１及び比較例２で調製した各フィルム層で被覆された製剤粒子０．１ｇ及び製剤粒子０．１ｇをゼラチンカプセルに封入し、４０℃７５％ＲＨ環境下にてアルミピロー包装して１カ月、３カ月、６カ月間保存したものを用い、日本薬局方のパドル法（試験液：水，パドル回転数５０ｒｐｍ）によって溶出性を調べた。結果を図１〜５に示す。
（２）結果
図３及び図４より、比較例１では、１次フィルム層（保護膜）を施した製剤粒子に対して１５質量％のフィルム層を施した場合でも、９０分後の薬物溶出率が２０〜５０％，１２０分後の薬物溶出率が３０〜６０％及び３００分後の薬物溶出率が８０％以上とならず、徐放性製剤における徐放化製剤粒子としては十分に機能しないと考えられる。そして、さらにコーティング量を増やし、厚いフィルム層を施したとしても十分な溶出制御は示すことはないと予測される。一方、比較例２では、１次フィルム層（保護膜）を施した製剤粒子に対して５質量％のフィルム層を施した場合において、９０分後の薬物溶出率が２０〜５０％，１２０分後の薬物溶出率が３０〜６０％及び３００分後の薬物溶出率が８０％以上とならず、徐放性製剤における徐放化製剤粒子としては十分に機能しないと考えられる。そして、さらにコーティング量を減らし、薄いフィルム層を施した場合、安定した溶出制御が困難となることが予測される。
一方、図１及び２より、実施例１及び２では、１次フィルム層（保護膜）を施した製剤粒子に対してフィルム層を施した場合に、９０分後の薬物溶出率が２０〜５０％，１２０分後の薬物溶出率が３０〜６０％及び３００分後の薬物溶出率が８０％以上となり、徐放性製剤における徐放化製剤粒子として十分に機能することが窺われる。
また、図５より、製剤粒子をゼラチンカプセルに封入し、４０℃７５％ＲＨ環境下にてアルミピロー包装して保存したものについても、アンブロキソール塩酸塩の溶出率に変化は無く、徐放性製剤における徐放化製剤粒子として十分に機能することが窺われる。
（３）考察
試験例１の結果より、比較例１のフィルム層で被覆された製剤粒子に比し、実施例１、２のフィルム層で被覆された製剤粒子では、アンブロキソール塩酸塩の溶出が明らかに遅延しており、フィルムコーティング量を適宜に調整し、フィルム層の厚みを変えることによって、多様なパターンの徐放性製剤における徐放化製剤粒子を提供できると考えられる。また、比較例２のフィルム層で被覆された製剤粒子では、さらに薄いフィルム層の形成が徐放性製剤に必要であり、恒常的に生産するためには技術的に困難である。
Test Example 1 Dissolution Test (1) Method 0.1 g of formulation particles and 0.1 g of formulation particles coated with each film layer prepared in Example 1, Example 2, Comparative Example 1 and Comparative Example 2 were enclosed in a gelatin capsule. Elution is performed using the Japanese Pharmacopoeia paddle method (test solution: water,
(2) Results From FIG. 3 and FIG. 4, in Comparative Example 1, drug dissolution after 90 minutes was observed even when a 15% by mass film layer was applied to the preparation particles subjected to the primary film layer (protective film). Rate is 20-50%, drug elution rate after 120 minutes is 30-60%, and drug elution rate after 300 minutes is not more than 80%, and functions sufficiently as sustained release preparation particles in sustained release preparations It is thought not to. Further, even if the coating amount is increased and a thick film layer is applied, it is predicted that sufficient elution control will not be shown. On the other hand, in Comparative Example 2, the drug elution rate after 90 minutes was 20 to 50% and 120 minutes when a film layer of 5% by mass was applied to the preparation particles subjected to the primary film layer (protective film). The drug elution rate after 30 to 60% and the drug elution rate after 300 minutes are not 80% or more, and it is considered that the sustained release preparation particles in the sustained release preparation do not function sufficiently. And when the coating amount is further reduced and a thin film layer is applied, stable elution control is expected to be difficult.
On the other hand, as shown in FIGS. 1 and 2, in Examples 1 and 2, when the film layer is applied to the preparation particles subjected to the primary film layer (protective film), the drug elution rate after 90 minutes is 20 to 50. %, The drug elution rate after 120 minutes is 30 to 60%, and the drug elution rate after 300 minutes is 80% or more, which indicates that it functions sufficiently as sustained-release preparation particles in sustained-release preparations.
In addition, as shown in FIG. 5, there was no change in the dissolution rate of ambroxol hydrochloride and the sustained release of the product particles encapsulated in gelatin capsules and stored in an aluminum pillow package at 40 ° C. and 75% RH. It appears to function well as sustained-release preparation particles in a pharmaceutical preparation.
(3) Consideration From the results of Test Example 1, the dissolution of ambroxol hydrochloride in the preparation particles coated with the film layer of Examples 1 and 2 as compared with the preparation particle coated with the film layer of Comparative Example 1 However, it is considered that sustained-release preparation particles in various patterns of sustained-release preparations can be provided by appropriately adjusting the film coating amount and changing the thickness of the film layer. Moreover, in the preparation particle | grains coat | covered with the film layer of the comparative example 2, formation of a still thinner film layer is required for a sustained-release preparation, and it is technically difficult to produce constantly.
本発明により、アンブロキソール又はその塩を含有し、アンブロキソールの溶出が制御され、その薬効が持続する錠剤、カプセル剤、散剤、顆粒剤等の実用化が期待される。 According to the present invention, the practical application of tablets, capsules, powders, granules and the like that contain ambroxol or a salt thereof, control the dissolution of ambroxol, and maintain its medicinal effect is expected.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2011100277A JP6084355B2 (en) | 2010-05-06 | 2011-04-28 | Ambroxol-containing preparation particles |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2010106158 | 2010-05-06 | ||
| JP2010106158 | 2010-05-06 | ||
| JP2011100277A JP6084355B2 (en) | 2010-05-06 | 2011-04-28 | Ambroxol-containing preparation particles |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2011251959A true JP2011251959A (en) | 2011-12-15 |
| JP2011251959A5 JP2011251959A5 (en) | 2014-05-08 |
| JP6084355B2 JP6084355B2 (en) | 2017-02-22 |
Family
ID=45416214
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2011100277A Active JP6084355B2 (en) | 2010-05-06 | 2011-04-28 | Ambroxol-containing preparation particles |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP6084355B2 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014181390A1 (en) * | 2013-05-08 | 2014-11-13 | 全星薬品工業株式会社 | Functional polymer film-coated particle having high drug content, tablet containing same, and methods for production thereof |
| KR20140145508A (en) * | 2013-06-13 | 2014-12-23 | 한미약품 주식회사 | Oral liquid formulation having improved stability comprising ambroxol and levodropropizine |
| CN104606170A (en) * | 2015-02-04 | 2015-05-13 | 上海华源安徽仁济制药有限公司 | Ambroxol hydrochloride capsule and preparation method thereof |
| CN107569473A (en) * | 2017-09-28 | 2018-01-12 | 南京易亨制药有限公司 | A kind of Sustained Release Ambroxol Hydrochloride Capsules and preparation method thereof |
| CN111135152A (en) * | 2020-01-19 | 2020-05-12 | 安徽省先锋制药有限公司 | Preparation method of ambroxol hydrochloride capsule |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63192725A (en) * | 1987-02-06 | 1988-08-10 | Shin Etsu Chem Co Ltd | Production of sustained release coated drug |
| JPH05320044A (en) * | 1991-12-11 | 1993-12-03 | Therapicon Srl | Pharmaceutical composition wherein release is programmed |
| JPH06116140A (en) * | 1992-10-06 | 1994-04-26 | Nitsusui Seiyaku Kk | Sustained release granule |
| JPH09315969A (en) * | 1996-05-24 | 1997-12-09 | Taiyo Yakuhin Kogyo Kk | Ibudilast-containing sustained release medicinal composition and its production |
| JPH11139960A (en) * | 1997-09-05 | 1999-05-25 | Takeda Chem Ind Ltd | Medicine |
| JPH11209306A (en) * | 1998-01-20 | 1999-08-03 | Nichiko Pharmaceutical Co Ltd | Production of sustained-release preparation containing medicine in high proportion |
| JP2000001429A (en) * | 1998-04-17 | 2000-01-07 | Taisho Pharmaceut Co Ltd | Multiple-unit type sustained release tablet |
| JP2002370968A (en) * | 2001-06-12 | 2002-12-24 | Towa Yakuhin Kk | Medicament-containing sustained-release granule and tablet containing the same |
| JP2004161653A (en) * | 2002-11-12 | 2004-06-10 | Dainippon Pharmaceut Co Ltd | Multiple unit type sustained-release preparation |
| JP2008201706A (en) * | 2007-02-20 | 2008-09-04 | Kowa Pharmaceutical Co Ltd | Small-sized sustained release tablet |
-
2011
- 2011-04-28 JP JP2011100277A patent/JP6084355B2/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63192725A (en) * | 1987-02-06 | 1988-08-10 | Shin Etsu Chem Co Ltd | Production of sustained release coated drug |
| JPH05320044A (en) * | 1991-12-11 | 1993-12-03 | Therapicon Srl | Pharmaceutical composition wherein release is programmed |
| JPH06116140A (en) * | 1992-10-06 | 1994-04-26 | Nitsusui Seiyaku Kk | Sustained release granule |
| JPH09315969A (en) * | 1996-05-24 | 1997-12-09 | Taiyo Yakuhin Kogyo Kk | Ibudilast-containing sustained release medicinal composition and its production |
| JPH11139960A (en) * | 1997-09-05 | 1999-05-25 | Takeda Chem Ind Ltd | Medicine |
| JPH11209306A (en) * | 1998-01-20 | 1999-08-03 | Nichiko Pharmaceutical Co Ltd | Production of sustained-release preparation containing medicine in high proportion |
| JP2000001429A (en) * | 1998-04-17 | 2000-01-07 | Taisho Pharmaceut Co Ltd | Multiple-unit type sustained release tablet |
| JP2002370968A (en) * | 2001-06-12 | 2002-12-24 | Towa Yakuhin Kk | Medicament-containing sustained-release granule and tablet containing the same |
| JP2004161653A (en) * | 2002-11-12 | 2004-06-10 | Dainippon Pharmaceut Co Ltd | Multiple unit type sustained-release preparation |
| JP2008201706A (en) * | 2007-02-20 | 2008-09-04 | Kowa Pharmaceutical Co Ltd | Small-sized sustained release tablet |
Non-Patent Citations (2)
| Title |
|---|
| PHARM TECH JAPAN, vol. 22, no. 8, JPN6015009703, 2006, pages 73 - 78, ISSN: 0003026090 * |
| 医薬品製剤化方略と新技術, JPN6015009704, 2007, pages 219 - 224, ISSN: 0003026091 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014181390A1 (en) * | 2013-05-08 | 2014-11-13 | 全星薬品工業株式会社 | Functional polymer film-coated particle having high drug content, tablet containing same, and methods for production thereof |
| JP5758552B2 (en) * | 2013-05-08 | 2015-08-05 | 全星薬品工業株式会社 | High content drug particles coated with functional polymer film, tablet containing the same, and production method thereof |
| US20160120813A1 (en) * | 2013-05-08 | 2016-05-05 | Powrex Corporation | Functional polymer film-coated particle having high drug content, tablet containing same, and methods for production thereof |
| US9693965B2 (en) | 2013-05-08 | 2017-07-04 | Powerex Corporation | Functional polymer film-coated particle having high drug content, tablet containing same, and methods for production thereof |
| KR20140145508A (en) * | 2013-06-13 | 2014-12-23 | 한미약품 주식회사 | Oral liquid formulation having improved stability comprising ambroxol and levodropropizine |
| KR102083621B1 (en) | 2013-06-13 | 2020-03-02 | 한미약품 주식회사 | Oral liquid formulation having improved stability comprising ambroxol and levodropropizine |
| CN104606170A (en) * | 2015-02-04 | 2015-05-13 | 上海华源安徽仁济制药有限公司 | Ambroxol hydrochloride capsule and preparation method thereof |
| CN107569473A (en) * | 2017-09-28 | 2018-01-12 | 南京易亨制药有限公司 | A kind of Sustained Release Ambroxol Hydrochloride Capsules and preparation method thereof |
| CN111135152A (en) * | 2020-01-19 | 2020-05-12 | 安徽省先锋制药有限公司 | Preparation method of ambroxol hydrochloride capsule |
Also Published As
| Publication number | Publication date |
|---|---|
| JP6084355B2 (en) | 2017-02-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5461179B2 (en) | Cellulosic micronucleus particles and method for producing the same | |
| JPS62103012A (en) | Multi-layered granule | |
| JP6084355B2 (en) | Ambroxol-containing preparation particles | |
| SA515360425B1 (en) | Oral formulations of deferasirox | |
| JPWO2006080481A1 (en) | Multiple unit type oral sustained-release preparation and method for producing the same | |
| WO2014030204A1 (en) | Medicament-containing hollow particle | |
| EP1109535A1 (en) | Extended release acetaminophen | |
| JP5973170B2 (en) | Solid molecular dispersion | |
| JP7083855B2 (en) | Glucose pellets, their preparation methods and their use | |
| AU2009315449B2 (en) | Novel method for preparing granulates of active principles, and granulates obtained thereof | |
| CN107412198A (en) | Duloxetine hydrochloride enteric slow release granule and preparation method thereof | |
| JP2017075139A (en) | Orally disintegrating tablet containing low-dose drug | |
| WO2012091049A1 (en) | Orally disintegrating tablet | |
| CN114748443A (en) | Memantine hydrochloride sustained-release pellet and preparation method thereof | |
| WO2017093890A1 (en) | Clobazam tablet formulation and process for its preparation | |
| JP5668317B2 (en) | Pseudoephedrine-containing preparation particles | |
| US9333170B2 (en) | Polyvalent polymeric matrix for modified release solid oral preparations and method of preparation thereof | |
| Rathnanand et al. | Formulation and in vitro evaluation of floating pulsatile tablets of nizatidine for chronotherapy of ulcers | |
| Kibria et al. | Formulation and evaluation of domperidone pellets prepared by powder layering technology | |
| UA127768C2 (en) | A process for the preparation of a modified release multiple unit oral dosage form of doxylamine succinate and pyridoxine hydrochloride | |
| JP2001139469A (en) | Novel sustained release preparation composite | |
| JP2019131614A (en) | Solid preparation | |
| CN103565766A (en) | Mesalazine enteric-coated sustained release tablet | |
| JP6307874B2 (en) | Layering particles | |
| Hadi et al. | Design and in-vitro evaluation of multiparticulate drug delivery system of terbutaline sulphate for the treatment of nocturnal asthma |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140319 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20140319 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20150317 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20150818 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20151029 |
|
| A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20151105 |
|
| A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20151211 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20161117 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20170125 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6084355 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |